Study challenges our understanding of premature ageing

The study offers a new outlook on how mitochondrial dysfunction may contribute to aging by affecting cellular nucleotide pools.


Mitochondrial DNA (mtDNA) mutagenesis and nuclear DNA repair defects are considered cellular mechanisms of aging. mtDNA mutator mice with increased mtDNA mutagenesis show signs of premature aging. However, why patients with mitochondrial diseases or mice with other forms of mitochondrial dysfunction do not age prematurely remains unknown.

In a new study, scientists at the University of Eastern Finland have suggested that accelerated aging is the result of abnormal cell nucleotide levels and compromised nuclear DNA maintenance.

The study was conducted on the mtDNA Mutator mice that have an inactive DNA repair mechanism. These mice accumulated mtDNA mutations and present with accelerated aging, which has led scientists to believe that mtDNA mutagenesis drives aging. However, despite rigorous studies by several groups, no one has been able to show that the Mutator mice would present elevated oxidative stress.

By challenging previous theories on the role of oxidative stress and mtDNA mutations in aging, the study offers an alternative explanation for the Mutator mice aging, namely compromised nuclear DNA maintenance.

The prematurely-aging Mutator mice harbor a defective polymerase-gamma enzyme and present with pronounced mtDNA mutagenesis. Despite the existence of other mouse models with equivalent mtDNA mutagenic propensity, the Mutator mouse model is the only one manifesting accelerated aging.

Furthermore, progeria is not a clinical feature of mitochondrial disease patients, not even in those with the most severe mtDNA mutagenic profiles. Instead, the clinical picture of the mtDNA Mutator mice is remarkably similar to that of other mouse progeria models and human progeric syndromes with nuclear genome instability, with the most prominent defects in proliferating cells, and especially in stem and progenitor cells necessary for tissue regeneration.

Scientists found that- in addition to the mtDNA maintenance defects, the Mutator mice also manifest nuclear DNA defects, including replication fork stalling, increased DNA-breaks, and activation of DNA damage response pathways.

Scientists explained, “Nucleotides are the building blocks of DNA, and proper cellular nucleotide levels are critical for genome maintenance. Moreover, the cytoplasmic and mitochondrial nucleotide pools are interconnected. The researchers show that in the Mutator mice, the total cellular nucleotide levels are decreased while the mitochondrial nucleotide pools are increased, suggesting preferential usage of nucleotides in the mitochondria. Indeed, the replication of mtDNA is drastically accelerated in the cells of the Mutator mice.”

The study is published in Nature Metabolism.

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